Therapeutic composition and process of making it



Patented Feb. 18, 1941 PATENT OFFICE THERAPEUTIC COMPOSITION AND. PROCESS OF MAKING IT David Alymer Scott, Forest Hill, and Albert Madden Fisher, Toronto, Ontario, Canada, assign ors to The Governors of the University of Toronto, Toronto, Ontario, Canada No Drawing. Application September 22, 1938, Serial No. 231,236

7 Claims. (01. 167-45) This application is a continuation in part of our application Serial No. 135,106, filed April 5, 1937.

It is the object of our present invention to enhance the utility of Insulin-histone compositions.

It has been demonstrated that the blood-sugarlowering action of Insulin may be prolonged by using with the Insulin such substances as pro- 10 tamine, histone, and (in some animals) spermine. At certain hydrogen-ion concentrations, the substances named form with the Insulin insoluble precipitates which, as experience shows, often adhere to the inside-of containers in which the compositions are stored. Further, these precipitates commonly form undesirably large aggregates which can not readily be adequately disintegrated. This tendency of the Insulin compositions to adhere to the walls of the containers and to form aggregates interferes with satisfactory use of the preparations; since, as is obvious, the precipitate, should remain completely and homogeneously suspended during withdrawal oi doses of the compositions.

We have discovered that the disadvantageous features noted above can be avoided, and in consequence the utility of the Insulin compositions can be enhanced, by having present in the compositions an adequate amount of metal of the class consisting of zinc, cadmium, nickel, and cobalt. Also we have discovered that by the presence of this amount of metal of the class defined the period of utility of the Insulin compositions is greatly lengthened. Moreover, we find that by the presence of this amount of either zinc or (sometimes) cadmium in the Insulin compositions the prolonged blood-sugar-lowering action of the compositions is extended. We here I assert no theory as to the nature of the actions of the metal present, or as to whether or not there is any chemical combination between the metal and either or both of the Insulin and the other component or components.

' This present application is directed to the us of these metals in connection with Insulinhistone preparations; for the use of those metals in connection with Insulin-protamine compositions is the subject of our Patent No. 2,179,384, granted November '7, 1939.

In preparing Insulin-histone compositions embodying our present invention we ensure the 7 presence in those compositions 01 an amount of v unit of Insulin in crystals of Insulin. (Insulin crystallized with zinc contains about 0.52% ct zinc, Insulin crystallized with cadmium contains about 0.77% of cadmium, Insulin crystallized with nickel contains about 0.41% of nickel, 6 and Insulin crystallized with cobalt contains about 0.44% of cobalt, in terms of dry weight of the crystals; and one milligram of a dry preparation of Insulin, whether in crystalline form or in substantially pure amorphous form, contains 10 between 20 and 25 international units, the units used on this Continent.) Beneficial results are obtainable by having present in the Insulinhlst'one compositions as little as half a milligram of zinc (or molecularly equivalent amounts it 15 the other metals are used) per thousand units of the Insulin; and desirably, in order to ensure that not less than this quantity of metal be present, we add at least this quantity. We may add any larger quantity of metal provided. only that the quantity added be not so large as to induce untoward reactions, such as undue pain Irom injections. We have obtained satisfactory results from adding 20 mg. of zinc (and also from adding molecularly equivalent quantities of the other metals) per 1000 units of Insulin. Most dew sirably we ensure the presence of a total 0! about 2 mg. of zinc per 1000 units of the Insulin.

Illustrations of our invention are as follows: 1. In any desired Way we makes. preparation of Insulin and histone, such as thymus histone,--as by adding the histoneto a solution of Insulin, commonly in the range of about 4 to mg. of histone per 1000 units of the Insulin. The histone employed may be prepared by any 35 suitable process, such, for example, as that described by Nelson (Arch. f. exper. Path. u. Pharour second. Instead of only one of these four metals, we may add two or more. Preferably we add metal of the defined class in the form of chlorides, but we may add metal in elemental form, or in other forms, such as acetates, oxides,

or hydroxides. Further, it is possible to ensure 50 metal has the function of preventing adherence and of their mixtures are not of prime importance.

In making such compositions available for clinical use, however, the hydrogen-ion concentration can be adjusted to control the character of the resultant product. If it is desired to administer the composition in the form of a suspension, a desirable reaction is on the alkaline side of the isoelectric point of Insulinsay a reaction between pH 6.9 and 7.4. If, on the other hand, it is desired that the composition be'in the form of a solution, the hydrogen-ion concentration should be kept on the acid side of the isoelectric point of Insulin-say at a reaction of about pH 4.0. If desired, a suitable buffer may be added to maintain the hydrogen-ion concentration at the determined reaction.

We claim as our invention:

1. The process of producing an Insulin-histone composition, which consists in putting Insulin and histone together, and ensuring the presence therewith of an amount of metal of the clas consisting of zinc, cadmium, nickel, and cobalt sufliclent to correspond molecularly to at least half a milligram of zinc per thousand units of the Insulin.

2. The process of producing an Insulin-histone composition, which consists in adding to Insulin a histone, and also adding metal of the class consisting of zinc, cadmium, nickel, and cobalt.

3. The process of producing an Insulin'-histone composition which consists in adding to Insulin a histone and zinc.

4. A composition of matter comprising Insulin, histone, and added metal of the class consisting of zinc, cadmium, nickel, and cobalt.

5. A composition oi matter, comprising Insulin, histone, and a quantity of metal of the class consisting of zinc, cadmium, nickel, and cobalt which per unit of Insulin is at least twice as large molecularly as the quantity of metal present per unit of Insulin in crystals of Insulin.

6. A composition of matter, comprising Insulin, histone, and added zinc.

'l. The process of producing an Insulin'-histone composition, which-consists in adding a histone toInsulin', and also adding metal oi. the class consisting of zinc, cadmium, nickel, and cobalt in sufiicient amountto make the total quantity of such metal present per unit of Insulin at least twice as large molecularly as the quantity 01' metal present per unit 0! Insulin in crystals 01 Insulin.

DAVID ALYMER SCOTT. ALBERT MADDEN FISHER. 

